03/09i Complement, Hypersensitivity I & II Flashcards
What are the three pathways of complement activation?
Classical
Lectin
Alternative/Spontaneous
At what point does the complement system get amplified?
C3
What are the functions of complement?
1) Opsonization and phagocytosis
2) Formation of the Membrane Attack Complex
3) Release of soluble inflammatory mediators C3a and C5a - chemoattractants, activate macrophages
What distinguishes the lectin complement pathway from the classical pathway?
Instead of using antibodies, it used mannose-binding lectins or ficolins to bind carbohydrates on pathogen surfaces
Why is the alternative pathway also considered the ‘spontaneous’ pathway?
C3 convertase can be activated spontaneously on cell surfaces
Does not require C1 or MBP
If complement can be activated spontaneously, why don’t we do it all the time?
Endogenous complement inhibitors - Decay Accelerating Factor (DAF), Membrane Cofactor Protein (MCP), and C1 Inhibitor
What are the anaphylatoxins?
C3a, C5a, and C4a - mediators of inflammation
Initiate inflammatory processes
Increase vascular permeability and smooth muscle contraction, histamine release from mast cells, chemotaxis, and cell activation
What are the functions of C5a?
Mediator of inflammation
Activation of phagocytosis by macrophages
What is the most common regulator of complement?
C1 inhibitor
Why doesn’t the Membrane Attack Complex work on our cells?
We have CD59, which inhibits its formation
What happens if you lack certain components of complement? List three complement deficiencies and their associated diseases
C1 Inhibitor deficiency - hereditary angioedema
C3 deficiency - recurrent infections, SLE
C2 and C4 deficiency - immune complex diseases
What are the two phases of a hypersensitivity reaction?
Sensitization phase
Elicitation phase
What are the four types of hypersensitivity reactions? By what antibodies or cells are they mediated?
Type 1 - immediate (IgE/mast cell)
Type 2 - antibody (IgG or IgM)
Type 3 - immune complex
Type 4 - T cell
What are the hallmarks of a Type 1 hypersensitivity reaction?
Activation of Th2 cells and production of IgE - inappropriate anti-helminthic-like response
IgE binds to mast cells
Re-exposure to the antigen results in release of mediators from mast cells, and subsequent effects
What are the mediators of Type 1 hypersensitivity? What are their effects?
Histamines - vasodilation, vascular permeability
Lipid mediators - bronchoconstriction, intestinal hypermotility, inflammation
Cytokines (TNF) - inflammation
Enzymes - tissue damage
What are some possibly causes of Type 1 hypersensitivity reactions?
Genetic propensity
Nature of the antigen
Hygiene hypothesis - lack of exposure to bugs!
What are the clinical manifestations of immediate hypersensitivity?
Rashes Sinus congestion Bronchial constriction Abdominal pain, diarrhea Systemic shock Anaphylaxis
What does the degree of immediate hypersensitivity reaction that develops depend upon?
Route of allergen exposure
Dose of allergen exposure
Frequency of allergen exposure
What are the characteristics of the immediate phase of Type 1 hypersensitivity?
Mast cell degranulation
Vascular response
Edema
What causes the immediate reaction of type 1 hypersensitivity?
Dependent on cross-linking of IgE and granule contents of mast cells
What is the Wheal and Flare Reaction?
Immediate phase of a Type 1 hypersensitivity reaction
Caused by injection of an allergen under the skin
Wheal = bump of inflammation, flare = vasodilation
What are the characteristics of the late phase of a type 1 hypersensitivity reaction?
Develops in 2-4 hours
Symptoms are due to the accumulation of inflammatory cells - neutrophils, eosinophils, basophils, and Th2 cells
May occur without a detectable immediate hypersensitivity reaction
What are some common examples of allergic diseases in humans? List five
Systemic anaphylaxis Bronchial asthma Allergic rhinitis Food allergies Urticaria and atopic dermatitis
What is anaphylaxis?
A systemic hypersensitivity reaction
Characterized by systemic edema, drop in blood pressure, vasodilation and increased permeability
Clinical symptoms - constriction of airways, laryngeal edema, hypermotility of the gut, outpouring of mucous, and hives
How is anaphylaxis treated?
Systemic epinephrine - reverses bronchoconstriction, improves cardiac output
Antihistamines
Steroids - prevent a late-phase reaction
What is bronchial asthma?
Intermittent and reversible airway obstruction caused by repeated immediate-phase hypersensitivity and late-phase allergic reactions in the lung
What are the characteristics of bronchial asthma?
Chronic bronchial inflammation
Bronchial smooth muscle cell hypertrophy and hyperreactivity
Increased production of thick mucous
What happens in the early phase of asthma?
Vasodilation
Bronchoconstriction
Mucous secretion
What happens in the late phase of asthma?
Inflammation and leukocyte activation
Tissue damage
Fibrosis and repair
How do you treat asthma?
Prevent mast cell degranulation
Bronchial relaxers
Leukotriene inhibitors
Corticosteroids to inhibit inflammatory reaction
What is urticaria?
An all-over acute wheal and flare reaction that occurs in response to direct contact with an allergen or when an allergen enters circulation
What is atopic dermatitis?
A late-phase reaction to an allergen in the skin mediated by Th2 cytokines (TNF, IL-4), which promote inflammation
Not inhibited by antihistamines
Can be blocked by corticosteroids
How are type I hypersensitivity reactions generally treated?
Avoidance
Pharmacologic agents - antihistamines, epinephrine, corticosteroids
Immunologic therapy - desensitization (allergy shots)
What causes type 2 hypersensitivity reactions?
Antibodies (IgG or IgM) that bind to antigens on particular cells or in particular tissues
Frequently involves self antibodies, due to a loss or lack of self-tolerance
Can be due to cross-reactive antigens
What are the two types of Type 2 hypersensitivity reactions? What mechanisms/cells are involved in each?
Non-cytolytic - involves antibody neutralization
Cytolytic - involves complement, macrophages, and NK cells
How do antibodies against tissue antigen cause disease? List three ways
1) Antibodies bind to normal cellular receptors or other proteins, and interfere with their function (without causing inflammation or tissue damage)
2) Antibodies directly opsonize cells or activate complement, leading to phagocytosis
3) Antibodies recruit neutrophils and macrophages, which cause tissue injury
What are four examples of non-cytolytic type 2 hypersensitivity reactions?
Myasthenia gravis
Graves’ disease
Insulin-resistant diabetes
Pernicious anemia
What is myasthenia gravis?
Caused by autoantibodies against nicotinic acetylcholine receptors, which blocks muscle contraction
Hallmark - progressive weakness and fatigue
Treatment - acetylcholinesterase inhibitors, immunosuppression
What is Graves’ disease?
Caused by agonistic antibodies which activate the thyroid-stimulating hormone receptor
Hallmark - hyperthyroidism, goiter, ophthalmopathy, and pretibial myxedema
Treatment - thyroid ablation
What is insulin resistant diabetes?
Caused by anti-insulin receptor autoantibodies, which inhibit insulin binding and cause severe insulin resistance
Hallmark - diabetes and acanthosis nigricans (skin lesion)
What is pernicious anemia?
Caused by autoantibodies against intrinsic factor, which is necessary for the absorption of vitamin B12
Hallmark - anemia that is unresponsive to B12 supplementation, often associated with chronic atrophic gastritis and autoimmune thyroid disease
Treatment - vitamin B12 shots
What are five examples of cytolytic type 2 hypersensitivities?
Autoimmune hemolytic anemia Autoimmune thrombocytopenia purpura Pemphigus vulgaris Goodpasture's syndrome Acute rheumatic fever
What is autoimmune hemolytic anemia?
Caused by a variety antibodies against antigens on RBCs
Response depends on the type of antibody - IgG leads to phagocytosis in the spleen, IgM leads to complement activation and RBC lysis
Can be caused by infections, drugs, and autoimmune diseases
What are the hallmarks of autoimmune hemolytic anemia?
Anemia Spherocytosis Reticulocytosis Elevated serum bilirubin and lactic dehydrogenase Increased urine hemoglobin
What causes acute transfusion reactions?
Antibody-mediated hemolysis (IgG and IgM)
What is Rh disease?
If an Rh- mother gives birth to an Rh+ fetus, the mother’s B cells become sensitizes to Rh antigen at the time of birth
During subsequent Rh+ pregnancies, the mother’s IgG will cross the placenta and attack the fetus
Treated with Rhogam
